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Case Presentation
74 y o Caucasian female, with hypertension and critical aortic stenosis. One year prior to presentation, aortic valve replacement had been attempted but was aborted due to severe aortic calcification, so called porcelain aorta. Now increasing symptoms of shortness of breath with exertion and chest pain, with recurrent hospital admissions for congestive heart failure.
Echocardiogram: LVEF >60% with concentric left ventricular hypertrophy and diastolic dysfunction. Mild mitral regurgitation. Moderate tricuspid regurgitation. Cardiac Catheterization: Normal systolic function. Non-obstructive coronary disease. CT Chest: Uniform, smooth calcification of the ascending aorta extending from the root to the origin of great vessels, with trivial atherosclerotic calcifications of the descending aorta. The appearance of the ascending aorta is reminiscent of aortic graft. Extensive aortic valve calcification and moderate mitral valve calcification.
Vascular layer
Intima
Atherosclerosis Renal Failure Diabetes Mnckebergs (Media sclerosis) Renal Failure Diabetes Diabetes
Media
Adventitia
Heart valves
Atherosclerosis
Intima
Calcification
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Mechanical stress analysis of a rigid inclusion in distensible material: a model of atherosclerotic calcification and plaque vulnerability. Hoshino et al. Am J Physiol 2009
Coronary Calcification
Detected by Electron Beam CT (EBCT) - Heart Scans
Atherosclerotic Plaques
Medial Calcification
CLINICAL IMPLICATIONS OF VASCULAR MEDIAL CALCIFICATION Aorta Correlates with increased ischemic episodes in peripheral vascular disease (PVD) Peripheral Arteries Strong marker for future cardiac events, PVD, and lower extremity amputations in diabetics Prognostic marker for all-cause and cardiovascular mortality in dialysis patients
Causes increased aortic stiffness, pulse pressure, left ventricular hypertrophy and cardiovascular mortality
Medial Calcification in Arteries of Dialysis Patients 30-700 fold increase in cardiovascular mortality risk in dialysis patients compared to the general population. Decreased survival in end stage renal disease patient with intimal and medial vascular calcification
Major cause of failure in native valves Major cause of failure in bioprosthetic valves Highly prevalent in patients with end stage renal failure
Active Inhibitors
Inhibitors
Promotors
Ca x Pi
VASCULAR CALCIFICATION
CIRCULATING NUCLEATIONAL COMPLEXES Apoptotic bodies Bisphosphonates OPG Bone Remodeling CELL DEATH
Matrix Vesicles
Ca x Pi
VASCULAR CALCIFICATION
CIRCULATING NUCLEATIONAL COMPLEXES Apoptotic bodies Bisphosphonates OPG Bone Remodeling CELL DEATH
Matrix Vesicles
Dependent on Vitamin K for correct gamma-carboxylation of glutamates (Gla-modifications) and anti-calcific activity
(Murshed 2004)
Dependent on specific proline and Gla-residues for BMP binding (Yao 2008) MGP loss of function mutations in humans cause Keutel syndrome (Keutel 1971, Munroe 1999)
MGP null
Aortic media
Wild type
Aortic media
Fetuin-deficient mouse after phosphate challenge Westenfeld et al. Trends Cardiovasc Med 2007
OSTEOPONTIN
Acidic phosphoprotein found in bone and teeth Inhibitor of apatite crystal growth Promotes osteoclast function
Ca x Pi
VASCULAR CALCIFICATION
CIRCULATING NUCLEATIONAL COMPLEXES Apoptotic bodies Bisphosphonates OPG Bone Remodeling CELL DEATH
Matrix Vesicles
Mineral Precipitation
Ca2+ PO42-
Cell Differentiation
osteoblast-like cell matrix vesicles
osteoid (matrix)
hydroxyapatite
Potential Origins of Osteoblast-like Cells in the Artery Wall Pericytes Mesenchymal stem cells Multipotent cells from the adventitia Resident cells in the media or intima Trans-differentiated SMC (Synthetic vs contractile phenotype)
UNDIFFERENTIATED
CONDENSATION
CALCIFIED NODULES
Ca x Pi
VASCULAR CALCIFICATION
CIRCULATING NUCLEATIONAL COMPLEXES Apoptotic bodies Bisphosphonates OPG Bone Remodeling CELL DEATH
Matrix Vesicles
Active Inhibitors
Intima
Atherosclerosis Renal Failure Diabetes Mnckebergs (Media sclerosis) Renal Failure Diabetes Diabetes
Media
Adventitia
Heart valves
Atherosclerosis
Hyperphosphatemia:
Major independent risk factor for vascular calcification and cardiovascular mortality in dialysis patients
(Block 1998, 2004, Goodman 2000, Shigematsu 2003, Young 2005)
Type III sodium-dependent phosphate co-transporters (Pit-1, Pit-2) Blockage of these transporters leads to phosphate induced SMC mineralization Pit-1 can be induced by BMP-2
Ca x Pi
VASCULAR CALCIFICATION
CIRCULATING NUCLEATIONAL COMPLEXES Apoptotic bodies Bisphosphonates OPG Bone Remodeling CELL DEATH
Matrix Vesicles
Degenerative Joint Diseases are Connection between Crystal diseases Vascular Calcification and Bone where synovial fibroblasts have an inflammatory response to the crystals.
Resorptive osteoclast-like cells are found in calcified atherosclerotic lesions. (Tintut et al. 2002) Maybe derived from blood monocytes
Osteoprotegerin (OPG)
OPG is a secreted protein that inhibits osteoclast formation OPG deficient mice have osteoporosis and arterial (medial) calcification
Bone Resorption in the Skeleton Often Coexists with Bone Formation in the Vasculature
Large Chunks
Engelse et al.2001
Degenerative Joint Diseases are Crystal diseases where synovial fibroblasts have an inflammatory response to the crystals.
The ingestion of BCP crystals by human monocyte-derived macrophages generates a pro-inflammatory response.
TNF-alpha
Large calcified areas may be less pro-inflammatory. How dangerous is the calcification we find on EBCT?